The esters of 4-(aminomethyl)benzoic acid are intermediates for the synthesis of active pharmaceutical ingredients. Since methyl esters can easily be hydrolyzed again, methyl 4-(aminomethyl)benzoate is of interest when mild conditions for the release of the acid function are sought in a synthesis sequence for the active ingredient.
For the preparation of methyl 4-(aminomethyl)benzoate, the literature already discloses various routes.
Methyl 4-(aminomethyl)benzoate is obtainable via the catalytic hydrogenation of methyl 4-cyanobenzoate (Synlett 10, 1623 (2001)), of the oxime (JP 1979-85926, JP 1973-136140) which is obtained from methyl 4-formylbenzoate and hydroxylamine, or of the imine formed from methyl 4-formylbenzoate and ammonia (JP 1977-104929).
In addition to hydrogen, it is also possible to use sodium borohydride in conjunction with cobalt(II) chloride (J. Am. Chem. Soc. 104, 6801 (1982)) or trifluoroacetic acid (Tetrahedron Lett. 33, 2875 (1976)) to reduce the 4-nitrile group or 4-amido group of the methyl benzoate.
SU 1989-4670483 also discloses that the para-amido group can also be reduced electrochemically to give the aminomethylene group.
Chem. Lett. 10, 1733 (1984) describes 4-methoxycarbonylbenzyl azide as a starting compound from which methyl 4-(aminomethyl)benzoate is obtained by treating with sodium hydrogen telluride.
It is likewise possible to synthesize methyl 4-(aminomethyl)benzoate by a chlorine/amine exchange on methyl parachloromethylbenzoate in nonaqueous media (JP 1972-75050).
In all aforementioned methods, the desired methyl ester group in the particular starting compound is already present. Owing to the reaction conditions, some of which are harsh, the methyl ester is, however, hydrolyzed again in an undesired manner actually during the reaction or the workup.
It is also possible, for the synthesis of the 4-(aminomethyl)benzoic ester, to start from the 4-(aminomethyl)benzoic acid available in commercial amounts and to esterify it with the corresponding alcohol.
J. Med. Chem. 37, (1994) discloses the esterification in the presence of hydrochloric acid in methanol boiling at reflux. However, the product is obtained as the hydrochloride and, owing to its corrosive properties, this greatly restricts the apparatus selection for the isolation of the solid.
In U.S. Pat. No. 6,172,084, instead of hydrochloric acid, hydrogen chloride is introduced into the methanolic reaction mixture, and the 4-(aminomethyl)benzoic acid is esterified by heating at reflux overnight. The reaction mixture is subsequently concentrated, admixed with saturated aqueous sodium carbonate solution and extracted three times with methylene chloride. The combined organic phases are dried with magnesium sulphate, freed of the desiccant by filtration and subsequently concentrated. Performance by this method on the industrial scale is not possible, since large amounts of magnesium sulphate are obtained, and are expensive to dispose of. Moreover, the yield achieved according to U.S. Pat. No. 6,172,084 is only about 57%.
The latter two methods for preparing methyl 4-(aminomethyl)benzoate are not satisfactory for performance on the industrial scale with regard to apparatus selection and ecological points of view. Moreover, the direct use of the hydrochloride obtained according to J. Med. Chem. 37, (1994) in a subsequent stage is not always possible and, in such cases, necessitates the preceding release in a further separate step, which impairs the economic attractiveness of the overall process. There is therefore a need for an easy-to-perform, economically viable and ecologically uncritical process for preparing 4-(aminomethyl)benzoic esters which is available for broad application.